Critical roles for the TSC-mTOR pathway in ?-cell function.

ABSTRACT: TSC1 is a tumor suppressor that associates with TSC2 to inactivate Rheb, thereby inhibiting signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as translation, in response to growth factors and nutrient signals. To test roles for TSC1 and mTORC1 in ?-cell function, we utilized Rip2/Cre to generate mice lacking Tsc1 in pancreatic ?-cells (Rip-Tsc1cKO mice). Although obesity developed due to hypothalamic Tsc1 excision in older Rip-Tsc1cKO animals, young animals displayed a prominent gain-of-function ?-cell phenotype prior to the onset of obesity. The young Rip-Tsc1cKO animals displayed improved glycemic control due to mTOR-mediated enhancement of ?-cell size, mass, and insulin production but not determinants of ?-cell number (proliferation and apoptosis), consistent with an important anabolic role for mTOR in ?-cell function. Furthermore, mTOR mediated these effects in the face of impaired Akt signaling in ?-cells. Thus, mTOR promulgates a dominant signal to promote ?-cell/islet size and insulin production, and this pathway is crucial for ?-cell function and glycemic control.

SUBMITTER: Mori H 

PROVIDER: S-EPMC2781354 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature